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Background: Melanoma incidence has quadrupled since 1970 and melanoma is now the second most common cancer in individuals under 50. Targeted immunotherapies for melanoma now potentially enable long-term remission even in advanced melanoma, but these melanoma survivors require ongoing surveillance, with implications for NHS resources and significant social and psychological consequences for patients. Total skin self-examination (TSSE) can detect recurrence earlier and improve clinical outcomes but is underperformed in the UK. To support survivors, the Achieving Self-directed Integrated Cancer Aftercare (ASICA) intervention was developed to prompt and improve TSSE performance, with subsequent reporting of concerns and submission of skin photos to a Dermatology Nurse Practitioner (DNP). ASICA was delivered as a randomized pilot trial.Methods: This paper reports on process evaluation. Data on participants' demographics and the concerns they reported during the trial were tabulated and displayed using Microsoft Excel and SPSS. We explored which participants used ASICA, and how frequently, to report any skin concerns. We also determined how the interactions had worked in terms of quality of skin photographs submitted, clinical assessments made by the DNP, and the assessments and decisions made for each concern. Finally, we explored significant events occurring during the trial. Data on participants' demographics and the concerns they reported during the trial were tabulated and displayed using SPSS. A semi-structured interview was undertaken with the DNP to gain perspective on the range of concerns presented and how they were resolved.Results: Of 121 recruited melanoma patients receiving ASICA for 12 months, 69 participants submitted a total of 123 reports detailing 189 separate skin-related concerns and including 188 skin photographs. Where participants fully complied with follow-up by the DNP, concerns were usually resolved remotely, but 19 (10.1%) were seen at a secondary care clinic and 14 (7.4%) referred to their GP. 49 (25.9%) of concerns were not completely resolved due to partial non-compliance with DNP follow-up.Conclusion: Melanoma patients randomized to the ASICA intervention were able to report skin-related concerns that could be resolved remotely through interaction with a DNP. Feasibility issues highlighted by ASICA will support further development and optimization of this digital tool.Trial Registration: Clinical Trials.gov , NCT03328247 . Registered on 1 November 2017. [ABSTRACT FROM AUTHOR]

Background: Misophonia is a condition marked by dysregulated emotions and behaviors in response to trigger sounds, often chewing, breathing, or coughing. Evidence suggests that misophonia develops in adolescence and the emotions and behaviors are a conditioned response to distress, resulting in social avoidance, stress, and family conflict. In addition, co-occurrence with other psychiatric illnesses such as anxiety, OCD, and Tourette syndrome is common. A transdiagnostic cognitive behavioral therapeutic (CBT) approach appears appropriate. There are currently no controlled studies of youth with misophonia. The current paper describes the approach to a pilot randomized, blinded family-based treatment study for youth ages 8-16 years. Preliminary results from a pilot open trial also are described.Methods: A 2-phase dual site telehealth treatment study using a transdiagnostic CBT approach, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Children and Adolescents (UP-C/A; Ehrenreich-May et al., 2018), is proposed. Phase 1 consisted of a 4-case pilot of UP-C/A. Phase 2 includes a randomized trial comparing the UP-C/A to a standard relaxation and education protocol.Results: Preliminary results from the pilot show modest improvements in evaluator-rated misophonia symptoms on the Clinical Global Impression Severity and Improvement scales.Limitations: There is little research to inform evidence-based practice for youth with misophonia. Study limitations include lack of standardized misophonia assessment instruments and an absence of formal diagnostic criteria.Conclusions: The current paper describes proposed methods for the first randomized controlled trial for youth with misophonia and their families along with results from a 4-case pilot. [ABSTRACT FROM AUTHOR]

Background: Psychotherapy for borderline personality disorder is often extensive and resource-intensive. Mentalisation-based therapy is a psychodynamically oriented treatment option for borderline personality disorder, which includes a case formulation, psychoeducation, and group and individual therapy. The evidence on short-term compared with long-term mentalisation-based therapy is currently unknown.Methods/design: The Short-Term MBT Project (MBT-RCT) is a single-centre, parallel-group, investigator-initiated, randomised clinical superiority trial in which short-term (20 weeks) will be compared with long-term (14 months) mentalisation-based therapy for outpatients with subthreshold or diagnosed borderline personality disorder. Outcome assessors, data managers, the data safety and monitoring committee, statisticians, and decision-makers will be blinded to treatment allocation. Participants will be assessed before randomisation and at 8, 16, and 24 months after randomisation. The primary outcome will be the severity of borderline symptomatology assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes will be functional impairment (Work and Social Adjustment Scale), quality of life (Short-Form Health Survey 36-mental component), global functioning (Global Assessment of Functioning), and proportion of participants with severe self-harm. In this paper, we present a detailed statistical analysis plan including a comprehensive explanation of the planned statistical analyses, methods to handle missing data, and assessments of the underlying statistical assumptions. Final statistical analyses will be conducted independently by two statisticians following the present plan.Discussion: We have developed this statistical analysis plan before unblinding of the trial results in line with the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice Guidelines, which should increase the validity of the MBT-RCT trial by mitigation of analysis bias.Trial Registration: ClinicalTrials.gov NCT03677037 . Registered on 19 September 2018. [ABSTRACT FROM AUTHOR]

Objective: Binge-eating disorder, the most prevalent eating disorder, is a serious public health problem associated with obesity, psychiatric and medical comorbidities, and functional impairments. Binge-eating disorder remains underrecognized and infrequently treated, and few evidence-based treatments exist. The authors tested the effectiveness of naltrexone-bupropion and behavioral weight loss therapy (BWL), alone and combined, for binge-eating disorder comorbid with obesity.Methods: In a randomized double-blind placebo-controlled trial conducted from February 2017 to February 2021, using a 2×2 balanced factorial design, 136 patients with binge-eating disorder (81.6% women; mean age, 46.5 years; mean BMI, 37.1) were randomized to one of four 16-week treatments: placebo (N=34), naltrexone-bupropion (N=32), BWL+placebo (N=35), or BWL+naltrexone-bupropion (N=35). Overall, 81.7% of participants completed independent posttreatment assessments.Results: Intention-to-treat binge-eating remission rates were 17.7% in the placebo group, 31.3% in the naltrexone-bupropion group, 37.1% in the BWL+placebo group, and 57.1% in the BWL+naltrexone-bupropion group. Logistic regression of binge-eating remission revealed that BWL was significantly superior to no BWL, and that naltrexone-bupropion was significantly superior to placebo, but there was no significant interaction between BWL and medication. Mixed models of complementary measures of binge-eating frequency also indicated that BWL was significantly superior to no BWL. The rates of participants attaining 5% weight loss were 11.8% in the placebo group, 18.8% in the naltrexone-bupropion group, 31.4% in the BWL+placebo group, and 38.2% in the BWL+naltrexone-bupropion group. Logistic regression of 5% weight loss and mixed models of percent weight loss both revealed that BWL was significantly superior to no BWL. Mixed models revealed significantly greater improvements for BWL than no BWL on secondary measures (eating disorder psychopathology, depression, eating behaviors, and cholesterol and HbA1c levels).Conclusions: BWL and naltrexone-bupropion were associated with significant improvements in binge-eating disorder, with a consistent pattern of BWL being superior to no BWL. [ABSTRACT FROM AUTHOR]

Introduction: This MONONOFU trial subgroup analysis evaluates the efficacy of lasmiditan across patient and migraine characteristics in Japanese patients with migraine.Methods: MONONOFU trial was a multicenter, randomized, double-blind, placebo-controlled study. The patients were randomly assigned in a 3:7:6:7 ratio to receive lasmiditan 50 mg, 100 mg, 200 mg, or placebo for a single migraine attack within 4 h of pain onset. Efficacy of lasmiditan vs placebo was evaluated at 2 h post dose for proportion of patients with headache pain freedom. Efficacy was assessed across patient characteristics (age, sex, body weight, cardiovascular risk factors (CVRF), and comorbidity of tension-type headache), migraine disease characteristics (history of migraine with aura, migraine prevention therapy, triptan response, and triptan use or nonuse), and migraine attack characteristics (headache severity, aggressive headache, attack during perimenstrual period, time to dosing, time of dosing, experienced treatment-emergent adverse event (TEAE) of dizziness, and experienced TEAE of somnolence). Logistic regression was used; all subgroup analyses were not analyzed with multiplicity-adjusted statistical tests.Results: Treatment-by-subgroup interactions (by each arm) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups and lasmiditan doses, except for CVRF (100 mg and 200 mg), migraine with aura (50 mg), triptan response (50 mg), and time to dosing (200 mg). Treatment-by-subgroup interactions (by overall) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups, except for CVRFs. Higher proportions of patients were pain free at 2 h post dose when treated with lasmiditan (50 mg, 100 mg, and 200 mg) versus placebo, irrespective of most patient characteristics, migraine disease characteristics, and migraine attack characteristics.Conclusion: Although few interactions were observed, lasmiditan could be a promising acute treatment option in a wide range of Japanese patients with migraine, as efficacy is not generally influenced by patient and migraine characteristics. [ABSTRACT FROM AUTHOR]

Introduction: Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed.Methods: Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.Results: A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.Conclusion: In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.Trial Registration: NCT03670810. [ABSTRACT FROM AUTHOR]

Importance: The use of spinal cord stimulation for chronic pain after lumbar spine surgery is increasing, yet rigorous evidence of its efficacy is lacking.Objective: To investigate the efficacy of spinal cord burst stimulation, which involves the placement of an implantable pulse generator connected to electrodes with leads that travel into the epidural space posterior to the spinal cord dorsal columns, in patients with chronic radiculopathy after surgery for degenerative lumbar spine disorders.Design, Setting, and Participants: This placebo-controlled, crossover, randomized clinical trial in 50 patients was conducted at St Olavs University Hospital in Norway, with study enrollment from September 5, 2018, through April 28, 2021. The date of final follow-up was May 20, 2022.Interventions: Patients underwent two 3-month periods with spinal cord burst stimulation and two 3-month periods with placebo stimulation in a randomized order. Burst stimulation consisted of closely spaced, high-frequency electrical stimuli delivered to the spinal cord. The stimulus consisted of a 40-Hz burst mode of constant-current stimuli with 4 spikes per burst and an amplitude corresponding to 50% to 70% of the paresthesia perception threshold.Main Outcomes and Measures: The primary outcome was difference in change from baseline in the self-reported Oswestry Disability Index (ODI; range, 0 points [no disability] to 100 points [maximum disability]; the minimal clinically important difference was 10 points) score between periods with burst stimulation and placebo stimulation. The secondary outcomes were leg and back pain, quality of life, physical activity levels, and adverse events.Results: Among 50 patients who were randomized (mean age, 52.2 [SD, 9.9] years; 27 [54%] were women), 47 (94%) had at least 1 follow-up ODI score and 42 (84%) completed all stimulation randomization periods and ODI measurements. The mean ODI score at baseline was 44.7 points and the mean changes in ODI score were -10.6 points for the burst stimulation periods and -9.3 points for the placebo stimulation periods, resulting in a mean between-group difference of -1.3 points (95% CI, -3.9 to 1.3 points; P = .32). None of the prespecified secondary outcomes showed a significant difference. Nine patients (18%) experienced adverse events, including 4 (8%) who required surgical revision of the implanted system.Conclusions and Relevance: Among patients with chronic radicular pain after lumbar spine surgery, spinal cord burst stimulation, compared with placebo stimulation, after placement of a spinal cord stimulator resulted in no significant difference in the change from baseline in self-reported back pain-related disability.Trial Registration: ClinicalTrials.gov Identifier: NCT03546738. [ABSTRACT FROM AUTHOR]

This study aimed to compare the effects of extracorporeal shockwave therapy (ESWT) and high-intensity laser therapy (HILT) on pain, grip strength, and function in patients with lateral epicondylalgia. This prospective randomized controlled study included 42 patients (22 women and 20 men, mean age: 37) divided into 3 groups. The first group received physiotherapy (n = 14), the second received physiotherapy combined with ESWT (n = 14), and the third received physiotherapy combined with HILT (n = 14). All participants underwent 10 physiotherapy sessions for 2 weeks, 5 sessions per week. In addition to physiotherapy, the ESWT group received 4 ESWT sessions, 2 sessions per week, and the HILT group received 4 HILT sessions, 2 sessions per week. The outcomes were pain intensity as assessed by Visual Analog Scale, grip strength by hand dynamometer, and function by the Duruoz Hand Index and Patient-Rated Tennis Elbow Evaluation-Turkish version questionnaire. The participants were assessed at the beginning of the study (T1/week 0), at the end of treatment (T2/2nd week), and at follow-up (T3/6th week). At follow-up (T3), a significant improvement was observed in all outcomes compared to baseline (T1) in all groups (P < 0.05). Inter-group comparison of the mean differences between baseline and end values showed that the HILT group was superior in all outcomes (P < 0.05). This study showed that physiotherapy alone combined with ESWT and HILT positively affected the treatment of lateral epicondylalgia. Physiotherapy combined with HILT was found to be the most effective for improving pain, grip strength, and function. Clinical trial number: NCT674325. [ABSTRACT FROM AUTHOR]

Background: Telepsychiatry Collaborative Care (TCC) and Telepsychiatry/Telepsychology Enhanced Referral (TER) expand the reach of specialty mental health services to underserved populations.Objective: Assess clinical predictors of treatment engagement for complex psychiatric conditions in TCC-in which remote specialists consult with primary care teams via an onsite care manager who also provides brief psychotherapy-and TER, in which remote specialists provide direct telehealth treatment.Design: A randomized pragmatic trial from twenty-four primary care clinics without onsite psychiatrists or psychologists.Participants: A total of 1,004 adult patients screened positive for posttraumatic stress disorder (PTSD)and/or bipolar disorder were randomized to receive TCC or TER for 1 year.Main Measures: Psychotherapy engagement was measured by the number of sessions completed, and pharmacotherapy engagement by the medication adherence item from the Schizophrenia Care and Assessment Program Health Questionnaire (SCAP-HQ).Key Results: Engagement in TCC psychotherapy visits was greater compared to TER. There was no association between the PTSD symptom severity and treatment engagement. The internal state scale (ISS) activation subscale, an indicator of mania, was associated with reduced odds of initiating psychotherapy (odds ratio [OR] = 0.70; 95% CI, 0.59 to 0.84) but not the number of sessions attended once psychotherapy started. The Drug Abuse Screening Test-10(DAST-10) score was associated with receipt of fewer psychotherapy sessions (incidence ratio rate [IRR] = 0.88; 95% CI, 0.81 to 0.95). The number of physical health comorbidities was associated with greater engagement in psychotherapy (IRR = 1.11, 95% CI, 1.03 to 1.19) and pharmacotherapy (OR = 1.54; 95% CI, 1.27 to 1.87). None of the findings varied by intervention group.Conclusions: Both teleintegrated and telereferral care offer an opportunity to treat patients with complex psychiatric conditions. While there was no difference in clinical characteristics predicting engagement, onsite care managers engaged patients in more psychotherapy sessions than remote therapists.Trial Registration: ClinicalTrials.gov Identifier: NCT02738944. [ABSTRACT FROM AUTHOR]

Objectives: To compare patient satisfaction, procedural variables, and safety with transradial access (TRA) and transfemoral access (TFA) in patients undergoing transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).Materials and Methods: From February 2019 to August 2021, 130 patients undergoing TACE for HCC were randomly allocated to the TRA (n = 65) or TFA (n = 65) group. Vascular closure devices were not used after TFA-TACE. All patients completed the post-catheterization questionnaire and 8-item Short-Form Health Survey 1 day after TACE.Results: Technical success rate, crossover rate, contrast agent dose, fluoroscopy time, procedure time, air kerma, dose-area product, length of hospital stay, and total cost were similar between the two groups (all p > 0.05). The incidence and severity of adverse events were also similar between the two groups (all p > 0.05). However, overall discomfort, difficulty going to the bathroom, difficulty feeding or self-caring, difficulty walking, general health, physical function, role physical function, social function, mental health, and role emotional function were better in the TRA group than in the TFA group (all p < 0.001). Consequently, more patients preferred the current access for their next procedure in the TRA group than in the TFA group (90.8% vs. 24.6%; p < 0.001).Conclusion: In patients undergoing TACE for HCC, using TRA instead of TFA can improve patient satisfaction without compromising procedural variables and safety.Key Points: • Transradial access (TRA) enabled early ambulation after transarterial chemoembolization (TACE), resulting in significant increase in activities of daily living and health-related quality of life (HRQoL) compared to transfemoral access (TFA) when vascular closure devices were not used. • Procedural variables (contrast agent dose, fluoroscopy time, procedure time, air kerma, dose-area product, length of hospital stay, and total cost) were not significantly different between patients who received TRA-TACE and TFA-TACE. • The incidence and severity of adverse events were similar between patients who received TRA-TACE and TFA-TACE. [ABSTRACT FROM AUTHOR]

Background: Tissue regeneration within the periodontally involved furcation area is one of the most challenging aspects of periodontal surgery. The aim of this study was to evaluate the additional benefit of leukocyte and platelet-rich fibrin (L-PRF) to autogenous bone grafts (ABGs) in the treatment of mandibular molar degree II furcation involvement, comparing the clinical outcomes with those from open flap debridement (OFD)+ABG and OFD alone treatments.Methods: Fifty-four patients, exhibiting one buccal or lingual mandibular molar furcation defect, were randomly assigned to three treatment groups: OFD+ABG+L-PRF (n = 18); OFD+ABG (n = 18); and OFD (n = 18). Clinical (probing depth [PD], horizontal clinical attachment level [HCAL], vertical clinical attachment level [VCAL], gingival recession [GR]) and radiographic (vertical bone level [VBL]) parameters were evaluated at baseline and 6 months after treatment. HCAL change was the primary outcome.Results: No significant differences within each group were reported for GR changes, but statistically significant improvements in HCAL, VCAL, PD, and VBL were observed in all groups, except for VBL in the OFD group. At 6 months, the mean HCAL gain was 2.29 ± 0.18 mm in the OFD+ABG+L-PRF group, which was significantly greater than that in the OFD+ABG (1.61 ± 0.18 mm) and OFD (0.86 ± 0.18 mm) groups. Both OFD+ABG+L-PRF and OFD+ABG therapies produced a significantly greater clinical and radiographic improvement than OFD.Conclusion: The addition of L-PRF to ABG produces a significantly greater HCAL gain and PD reduction as compared with OFD+ABG treatment in mandibular degree II furcation involvements. [ABSTRACT FROM AUTHOR]

Aims: Interventional cardiology procedures may expose patients and staff to considerable radiation doses. We aimed to assess whether exposure to ionizing radiation during catheter ablation of supraventricular tachycardia (SVT) can be completely avoided.Methods and Results: In this prospective randomized study, patients with SVT (atrioventricular re-entrant tachycardia n = 94, typical atrial flutter n = 29) were randomly assigned in a 1:1 ratio to catheter ablation with conventional fluoroscopic guidance (CF group) or with the EnSite Precision mapping system [zerofluoro (ZF) group]. Acute procedural parameters, increased stochastic risk of cancer incidence and 6-month follow-up data were assessed. Between May 2019 and August 2020, 123 patients were enrolled. Clinical parameters were comparable. Median procedural time was 60.0 and 58.0 min, median fluoroscopy time and estimated median effective dose were 240 s vs. 0 and 0.38 mSv vs. 0 and arrhythmia recurrence was 5% and 7.9% in the CF and ZF groups, respectively. The acute success rate was 98.4% in both groups. No procedure-related complications were reported. At an average age of 55.5 years and median radiation exposure of 0.38 mSv, the estimate of increased incidence was approximately 1 in 14 084. The estimated mortality rate was 1 per 17 857 exposed persons.Conclusions: The procedural safety and efficacy of the zero-fluoroscopic approach are similar to those of conventional fluoroscopy-based ablation for atrioventricular nodal re-entrant tachycardia and atrial flutter. Under the assumption of low radiation dose, the excessive lifetime risk of malignancy in the CF group due to electrophysiology procedure is reasonably small, whilst totally reduced in zero fluoroscopy procedures. [ABSTRACT FROM AUTHOR]

Background: Recent studies have proved the importance of intact lateral trochanteric wall, thus buttressing/fixing the broken lateral trochanteric wall irrespective of the implant, is likely to improve the alignment and outcome. We compared the outcome of lateral wall buttressing by trochanteric buttress plate (TBP) supplemented to proximal femoral nailing versus proximal femoral nailing alone in patients of broken lateral wall intertrochanteric fractures.Material and Method: Sixty patients of intertrochanteric factures (IT) of femur with broken lateral wall were randomized into group A or B and were treated with either proximal femoral nail (PFN) alone or proximal femoral nail augmented with trochanteric buttress plate (PFN + TBP), respectively. The TBP plate used was primarily fixed to proximal femur via 8 mm hip screw and 6.4 mm antirotation screw of the PFN. Operative time, blood loss, radiation exposure, quality of reduction, functional outcome, union time, and complications were compared.Result: The mean age was 60.03 + 7.60 (range 42 to 70 years), with male to female ratio of 4:1 and left to right ratio of approximately 1:1. The mean follow up in the series was 16.2 months (range 13 to 36 months). Mean duration of surgery, mean intra-operative blood loss, and mean number of exposures in group A (PFN alone) were 64.88 + 12.24 min (48 to 88), 93 + 1.18 ml (60 to 120), and 32.13 (24 to 46) and in group B (PFN with TBP plate) were 91.86 + 12.78 min (70 to 122 min), 144.8 + 3.6 ml (116 to 208 ml), and 56.6 (38 to 112), respectively. Twenty-five patients and 28 patients in groups A and B respectively achieved score of 4 Chang quality reduction. Mean union time was 13.4 weeks in group A whereas in group B was 11.6 weeks. Mean HHS score in group A was 87.86 with 90% patients in comparison to 94.13 and 97% cases having excellent to good results in group B. In group A, 24 patients, while 29 patients in group B, had excellent to good results. Four patients had hip pain, four had impingement of screws, two had screw migration, three had Z/reverse effect, and four patients had shortening of more than 1 cm in group A. In group B, only one patient had impingement and none of the patient had hip pain, infection, implant failure, Z effect, or shortening.Conclusion: The lateral trochanteric wall in IT fractures is significantly important, and when the lateral wall is broken, it can lead to poor results. TBP plate which is applied laterally on femur along with nail and fixing the plate with hip screw and antirotational screw provides faster union, early weight bearing, better reduction, and so better hip functions. TBP can be used successfully to augment, fix, or buttress the lateral trochanteric wall giving excellent to good results but at the cost of surgical time, blood loss, and radiation exposure. [ABSTRACT FROM AUTHOR]

Introduction: We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo.Methods: Subject-level data were derived from three randomized, double-blind, placebo- or NSAID-controlled trials of tanezumab in subjects with moderate-to-severe OA. Subjects received subcutaneous tanezumab (2.5 mg, n = 1527; 5 mg, n = 1279) every 8 weeks, oral NSAIDs (n = 994) daily, or placebo (n = 513). Group-based trajectory modeling (GBTM, an application of finite mixture statistical modeling that uses response trajectory to identify and summarize complex patterns in longitudinal data) was used to identify subgroups of subjects following similar patterns of response in each treatment arm, based on daily pain intensity scores from baseline through Week 16. We then examined whether subject-related variables were associated with any of the subgroups using multinomial logistic regression.Results: A three-subgroup/four-inflection point trajectory model was selected based on clinical and statistical considerations. The subgroups were high responders (substantial pain improvement and a large majority of members achieved ≥ 30% improvement before Week 16), medium responders (gradual pain improvement and a majority of members achieved ≥ 30% improvement by Week 16), and non-responders (little to no pain improvement over 16 weeks). Across all treatments, fluctuation in pain intensity in the week prior to treatment was consistently associated with treatment response. Other variables were positively (age, body mass index, days of rescue medication use) or negatively (severity of disease based on Kellgren-Lawrence grading) associated with response but effects were small and/or varied across treatments.Conclusions: Across all treatments, GBTM identified three subgroups of subjects that were characterized by extent of treatment response (high, medium, and non-responders). Similar analyses (e.g., grouping of subjects based on response trajectory and identification of subgroup-related variables) in other studies of OA could inform clinical trial design and/or treatment approaches. (NCT02697773; NCT02709486; NCT02528188). [ABSTRACT FROM AUTHOR]

Background: Problematic cocaine use remains a significant public health issue, particularly among women. However, no concerted efforts have been made to target a pharmacological treatment option for women with cocaine use disorder (CUD) despite preclinical, human laboratory, and a limited number of clinical studies demonstrating that progesterone can attenuate the effects of cocaine to a greater extent in women than men.Objectives: To evaluate the safety, tolerability, and preliminary efficacy of progesterone for treating women with CUD.Methods: A 10-week double-blind randomized treatment trial was conducted. Prior to randomization, participants were required to achieve cocaine abstinence (1 week) before assignment to progesterone (up to 400 mg/day) or placebo. The primary efficacy outcomes were days to relapse and cocaine abstinence during the last 3 weeks of the trial. The frequency of side effects was also assessed.Results: 227 women were assessed for eligibility. Twenty-five women entered treatment and 21 were randomized to progesterone (n = 11) or placebo (n = 10). The majority of women relapsed in less than 4 days with no differences between the two groups. Further, there were no significant differences between the progesterone and placebo groups in terms of cocaine abstinence during the last 3 weeks of the trial (27% and 10% respectively). The most commonly reported side effects were headache and fatigue, but no group differences were noted.Conclusions: Progesterone was well tolerated and safe and supports further study is in a larger sample to determine if exogenous progesterone is an effective treatment option for women with CUD.(ClinicalTrials.gov Identifier: NCT00632099). [ABSTRACT FROM AUTHOR]

Copyright of Climacteric is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Surgery is the property of CMA Impact Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rationale: Mouth breathing increases upper airway collapsibility, leading to decreased efficacy of obstructive sleep apnea (OSA) treatments. We hypothesized that the use of mandibular advancement devices (MAD) increases mouth breathing, and thus, using an adhesive mouthpiece (AMT) to prevent mouth breathing in combination with MAD can improve the treatment efficacy. Objectives: To evaluate the efficacy of MAD + AMT in comparison with MAD alone. Methods: A prospective crossover pilot study was designed to test this hypothesis. Briefly, adult participants with an apnea-hypopnea index (AHI) between 10 and 50 events/h at the screening visit were randomized to no treatment (baseline), MAD treatment, AMT treatment, and MAD + AMT treatment. As a primary analysis, absolute AHI was compared between MAD and MAD + AMT arms. Secondary analyses included quantifying the percent change in AHI, percentage of complete (AHI < 5 events/h) and incomplete (5-10 events/h) responders, and the efficacy of AMT alone in comparison with other treatment arms. Results: A total of 21 participants were included (baseline AHI = 24.3 ± 9.9 events/h). The median AHI (interquartile range) in the MAD and MAD + AMT arms were 10.5 (5.4-19.6) events/h and 5.6 (2.2-11.7) events/h (P = 0.02), respectively. A total of 76% of individuals achieved an AHI of <10 events/h in the MAD + AMT arm versus 43% in the MAD arm (P < 0.01). Finally, the observed effect was similar in moderate to severe OSA (AHI ⩾ 15 events/h) in terms of absolute reduction and treatment responders, and AMT alone did not significantly reduce the AHI compared with baseline. Conclusions: A combination of an adhesive mouthpiece and MAD is a more effective therapy than MAD alone. These findings may help improve clinical decision making in sleep apnea. [ABSTRACT FROM AUTHOR]

Objective: To estimate comparative healing rates and decision-making associated with the use of bacterial autofluorescence imaging in the management of diabetic foot ulcers (DFUs).Research Design and Methods: This is a single-center (multidisciplinary outpatient clinic), prospective pilot, randomized controlled trial (RCT) in patients with an active DFU and no suspected clinical infection. Consenting patients were randomly assigned 1:1 to either treatment as usual informed by autofluorescence imaging (intervention), or treatment as usual alone (control). The primary outcome was the proportion of ulcers healed at 12 weeks by blinded assessment. Secondary outcomes included wound area reduction at 4 and 12 weeks, patient quality of life, and change in management decisions after autofluorescence imaging.Results: Between November 2017 and November 2019, 56 patients were randomly assigned to the control or intervention group. The proportion of ulcers healed at 12 weeks in the autofluorescence arm was 45% (n = 13 of 29) vs. 22% (n = 6 of 27) in the control arm. Wound area reduction was 40.4% (autofluorescence) vs. 38.6% (control) at 4 weeks and 91.3% (autofluorescence) vs. 72.8% (control) at 12 weeks. Wound debridement was the most common intervention in wounds with positive autofluorescence imaging. There was a stepwise trend in healing favoring those with negative autofluorescence imaging, followed by those with positive autofluorescence who had intervention, and finally those with positive autofluorescence with no intervention.Conclusions: In the first RCT, to our knowledge, assessing the use of autofluorescence imaging in DFU management, our results suggest that a powered RCT is feasible and justified. Autofluorescence may be valuable in addition to standard care in the management of DFU. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulins are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment and high health-care costs. Our objective was to determine whether intravenous immunoglobulin withdrawal is non-inferior to continuing intravenous immunoglobulin treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, intravenous immunoglobulin-controlled non-inferiority trial in seven centres in the Netherlands (Trial registration: ISRCTN 13637698; www.isrctn.com/ISRCTN13637698). Adults with clinically stable chronic inflammatory demyelinating polyradiculoneuropathy using intravenous immunoglobulin maintenance treatment for at least 6 months were included. Patients received either intravenous immunoglobulin withdrawal (placebo) as investigational treatment or continuation of intravenous immunoglobulin treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-week follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale. The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse end point according to predefined criteria. Patients with a relapse end point after intravenous immunoglobulin withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable were included in an open-label extension phase of 52 weeks. We included 60 patients, of whom 29 were randomized to intravenous immunoglobulin withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change Inflammatory Rasch-Overall Disability Scale scores was -0.47 (95% CI -1.24 to 0.31), indicating that non-inferiority of intravenous immunoglobulin withdrawal could not be established. In the intravenous immunoglobulin withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the intravenous immunoglobulin continuation group (-17%; 95% CI -39 to 8). Of the intravenous immunoglobulin withdrawal group, 28% remained stable at the end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether intravenous immunoglobulin withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of intravenous immunoglobulin-treated patients experienced a relapse end point, emphasizing the need for more objective measures for disease activity in future trials, as the patient-reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients. [ABSTRACT FROM AUTHOR]

Background: Late-life depression is common, modifiable, yet under-treated. Service silos and human resources shortage contribute to insufficient prevention and intervention. We describe an implementation research protocol of collaborative stepped care and peer support model that integrates community mental health and aged care services to address service fragmentation, using productive ageing and recovery principles to involve older people as peer supporters to address human resource issue.Methods/design: This is a non-randomised controlled trial examining the effectiveness and cost-effectiveness of the "Jockey Club Holistic Support Project for Elderly Mental Wellness" (JC JoyAge) model versus care as usual (CAU) in community aged care and community mental health service units in 12 months. Older people aged 60 years and over with mild to moderate depressive symptoms or risk factors for developing depression will be included. JoyAge service users will receive group-based activities and psychoeducation, low-intensity psychotherapy, or high-intensity psychotherapy according to the stepped care protocol in addition to usual community mental health or aged care, with support from an older peer supporter. The primary clinical outcome, depressive symptoms, and secondary outcomes, self-harm risk, anxiety symptoms, and loneliness, will be measured with the Patient Health Questionnaire-9 (PHQ-9), Self-Harm Inventory, Generalized Anxiety Disorder 7-item scale (GAD-7), and UCLA Loneliness 3-item scale (UCLA-3) respectively. Cost-effectiveness analysis will assess health-related quality of life using the EQ-5D-5L and service utilisation using the Client Service Receipt Inventory (CSRI). We use multilevel linear mixed models to compare outcomes change between groups and calculate the incremental cost-effectiveness ratio in terms of quality-adjusted life years.Discussion: This study will provide evidence about outcomes for older persons with mental health needs receiving collaborative stepped care service without silos and with trained young-old volunteers to support engagement, treatment, and transitions. Cost-effectiveness findings from this study will inform resource allocation in this under-treated population.Trial Registration: ClinicalTrials.gov NCT03593889. Registered on 20 July 2018. [ABSTRACT FROM AUTHOR]

Background: Depression treatments are typically less effective for young people than for adults. However, treatments rarely target loneliness, which is a key risk factor in the onset, maintenance and development of depression.Aims: This study evaluated the efficacy of a novel loneliness intervention, Groups 4 Health (G4H), relative to the best-practice treatment of cognitive-behavioural therapy (CBT) in reducing loneliness and depression over a 12-month period (Australian New Zealand Clinical Trial Registry: ACTRN12618000440224).Method: The study was a phase 3 randomised non-inferiority trial comparing G4H with dose-controlled group CBT. Participants were 174 people aged 15-25 years experiencing loneliness and clinically significant symptoms of depression, who were not in receipt of adjunct treatment. Participants were recruited from mental health services in Southeast Queensland, Australia. Randomisation was conducted using computer software. Follow-up assessments and statistical analyses were masked to allocation. Both interventions consisted of five 75 min group-based psychotherapy sessions. The primary outcomes were depression and loneliness, with a non-inferiority margin of 2.20 for depression.Results: The trial enrolled 174 participants between 24 April 2018 and 25 May 2019, with 84 in the G4H condition and 90 in the CBT condition. All randomised participants were included in the intention-to-treat analyses (n = 174). The pre-post effect sizes for depression were dG4H = -0.71 and dCBT = -0.91. For loneliness, they were dG4H = -1.07 and dCBT = -0.89. At 12-month follow-up, the absolute difference between groups on depression was 1.176 (95% CI -1.94 to 4.29) and on loneliness it was -0.679 (95% CI -1.43 to 0.07). No adverse effects were observed.Conclusions: G4H was non-inferior to CBT for depression and showed a slight advantage over CBT for loneliness that emerged after treatment completion. [ABSTRACT FROM AUTHOR]

Background: Comatose patients admitted after resuscitation from cardiac arrest have a significant risk of poor outcome due to hypoxic brain injury. While numerous studies have investigated and challenged the target temperature as the efficacious part of the guideline endorsed Targeted Temperature Management (TTM) protocols, our knowledge and how the remaining parts of the TTM are optimized remain sparse. The present randomized trial investigated two aspects of the TTM protocol: target blood pressure during the ICU stay and oxygenation during mechanical ventilation. Furthermore, the efficacy of device-based post-TTM fever management is addressed.Methods: Investigator-initiated, dual-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Patients are eligible for inclusion if unconscious, older than 18 years of age, and have return of spontaneous circulation for more than 20 min.Intervention: allocation 1:1:1:1 into a group defined by (a) blood pressure targets in double-blind intervention targeting a mean arterial blood pressure of 63 or 77 mmHg and (b) restrictive (9-10 kPa) or liberal (13-14 kPa) of arterial oxygen concentration during mechanical ventilation. As a subordinate intervention, device-based active fever management is discontinued after 36 h or 72. Patients will otherwise receive protocolized standard of care according to international guidelines, including targeted temperature management at 36 °C for 24 h, sedation with fentanyl and propofol, and multimodal neuro-prognostication. Primary endpoint: Discharge from hospital in poor neurological status (Cerebral Performance category 3 or 4) or death, whichever comes first.Secondary Outcomes: Time to initiation of renal replacement therapy or death, neuron-specific enolase (NSE) level at 48 h, MOCA score at day 90, Modified Ranking Scale (mRS) and CPC at 3 months, NT-pro-BNP at 90 days, eGFR and LVEF at 90 days, daily cumulated vasopressor requirement during ICU stay, and need for a combination of vasopressors and inotropic agents or mechanical circulatory support.Discussion: We hypothesize that low or high target blood pressure and restrictive and liberal oxygen administration will have an impact on mortality by reducing the risk and degree of hypoxic brain injury. This will be assessment neurological outcome and biochemical and neuropsychological testing after 90 days.Trial Registration: ClinicalTrials.gov NCT03141099. Registered on May 2017 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Background: Many studies have reported high efficacy and safety of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) when administered under direct observation in Cameroon. There is paucity of data to support their continuous use in home-based treatment of uncomplicated Plasmodium falciparum malaria in Cameroon. Hence, this study aimed to assess the effectiveness and safety of AS-AQ versus AL for home-based treatment of uncomplicated P. falciparum malaria among children 6-120 months in Yaoundé, Cameroon.Methods: A two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) was carried out from May 2019 to April 2020 at two secondary hospitals in Yaoundé. Participants were randomized to receive either AS-AQ or AL. After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff. The conventional on-treatment and post-treatment laboratory and clinical evaluations were not done until day 3 of the full antimalarial treatment course. The evaluation of effectiveness was mainly based on per protocol polymerase chain reaction adjusted adequate clinical and parasitological response (PP PCR adjusted ACPR) on day 28 post-treatment. Safety was based on assessment of adverse events (AEs) and severe adverse events (SAEs) from day 1 to day 28.Results: A total of 242 children were randomized to receive AS-AQ (n = 114) and AL (n = 128). The PP PCR adjusted day 28 cure rates were [AS-AQ = 96.9% (95% CI, 91.2-99.4) versus AL = 95.5% (95% CI, 89.9-98.5), P = 0.797]. Expected mild to moderate adverse events were reported in both arms [AS-AQ = 83 (84.7%) versus AL = 99 (86.1%), P = 0.774]. The most common adverse events included: transient changes of hematologic indices and fever.Conclusions: This study demonstrated that AS-AQ and AL are effective and safe for home management of malaria in Yaoundé. The evidence from this study supports the parallel use of the two drugs in routine practice. However, the findings from this study do not describe the likely duration of antimalarial effectiveness in holoendemic areas where multiple courses of treatment might be required.Trial Registration: This study is a randomized controlled trial and it was retrospectively registered on 23/09/2020 at ClinicalTrials.gov with registration number NCT04565184. [ABSTRACT FROM AUTHOR]

Importance: Out-of-hospital cardiac arrest (OHCA) has poor outcome. Whether intra-arrest transport, extracorporeal cardiopulmonary resuscitation (ECPR), and immediate invasive assessment and treatment (invasive strategy) is beneficial in this setting remains uncertain.Objective: To determine whether an early invasive approach in adults with refractory OHCA improves neurologically favorable survival.Design, Setting, and Participants: Single-center, randomized clinical trial in Prague, Czech Republic, of adults with a witnessed OHCA of presumed cardiac origin without return of spontaneous circulation. A total of 256 participants, of a planned sample size of 285, were enrolled between March 2013 and October 2020. Patients were observed until death or day 180 (last patient follow-up ended on March 30, 2021).Interventions: In the invasive strategy group (n = 124), mechanical compression was initiated, followed by intra-arrest transport to a cardiac center for ECPR and immediate invasive assessment and treatment. Regular advanced cardiac life support was continued on-site in the standard strategy group (n = 132).Main Outcomes and Measures: The primary outcome was survival with a good neurologic outcome (defined as Cerebral Performance Category [CPC] 1-2) at 180 days after randomization. Secondary outcomes included neurologic recovery at 30 days (defined as CPC 1-2 at any time within the first 30 days) and cardiac recovery at 30 days (defined as no need for pharmacological or mechanical cardiac support for at least 24 hours).Results: The trial was stopped at the recommendation of the data and safety monitoring board when prespecified criteria for futility were met. Among 256 patients (median age, 58 years; 44 [17%] women), 256 (100%) completed the trial. In the main analysis, 39 patients (31.5%) in the invasive strategy group and 29 (22.0%) in the standard strategy group survived to 180 days with good neurologic outcome (odds ratio [OR], 1.63 [95% CI, 0.93 to 2.85]; difference, 9.5% [95% CI, -1.3% to 20.1%]; P = .09). At 30 days, neurologic recovery had occurred in 38 patients (30.6%) in the invasive strategy group and in 24 (18.2%) in the standard strategy group (OR, 1.99 [95% CI, 1.11 to 3.57]; difference, 12.4% [95% CI, 1.9% to 22.7%]; P = .02), and cardiac recovery had occurred in 54 (43.5%) and 45 (34.1%) patients, respectively (OR, 1.49 [95% CI, 0.91 to 2.47]; difference, 9.4% [95% CI, -2.5% to 21%]; P = .12). Bleeding occurred more frequently in the invasive strategy vs standard strategy group (31% vs 15%, respectively).Conclusions and Relevance: Among patients with refractory out-of-hospital cardiac arrest, the bundle of early intra-arrest transport, ECPR, and invasive assessment and treatment did not significantly improve survival with neurologically favorable outcome at 180 days compared with standard resuscitation. However, the trial was possibly underpowered to detect a clinically relevant difference.Trial Registration: ClinicalTrials.gov Identifier: NCT01511666. [ABSTRACT FROM AUTHOR]

Background: Cardiac remodeling following myocardial infarction is a pathological process. We aimed to examine the effect of early short-term minocycline on the left ventricular function following ST-elevation myocardial infarction treated by the primary percutaneous coronary intervention.Methods: In this double-blind, randomized controlled trial, data of 73 patients STEMI patients who were candidates for primary PCI were enrolled. Patients were then randomized to receive minocycline 50 mg orally, followed by 50 mg once a day for 5 days or a placebo with the same schedule. Measurement of serum matrix metalloproteinase-9 (MMP-9) and 2-dimensional speckle tracking echocardiography was performed at baseline and between 4 and 6 months after discharge. Then the demographic, clinical, echocardiographic, and angiographic data, as well as the levels of MMP-9, were compared between the study groups.Results: There was no statistically significant difference between the study groups regarding the baseline characteristics. Serum levels of MMP-9 did not change following the intervention within each group and were not significantly different between the groups after follow-up. In the follow-up echocardiography, we also did not observe any difference between the two groups CONCLUSION: In this study, we did not observe any effect of minocycline on cardiac remodeling based on 2-dimensional speckle tracking echocardiography and MMP-9 levels.Trial Registration: Iranian Registry of Clinical Trials IRCT201411188698N15 . Registered on 22 June 2015, prospectively. [ABSTRACT FROM AUTHOR]

Objective: A first-in-human responsive deep brain stimulation (rDBS) trial (NCT03868670) for obesity is under way, which is based on promising preclinical evidence. Given the upfront costs of rDBS, it is prudent to examine the success threshold for cost-effectiveness compared with laparoscopic Roux-en-Y gastric bypass (LRYGB).Methods: Efficacy and safety data on LRYGB and safety data on rDBS were collected for established indications through a literature search. The success threshold was defined as minimum BMI reduction. Treatment costs were calculated via Medicare national reimbursement data.Results: LRYGB had a mean BMI reduction of 13.75 kg/m2 . Based on adverse events, LRYGB was a less-preferred health state (overall adverse event utility of 0.96 [0.02]) than rDBS (0.98 [0.01]), but LRYGB ($14,366 [$6,410]) had a significantly lower treatment cost than rDBS ($29,951 [$4,490]; p < 0.0001). Therefore, for rDBS to be cost-effective compared with LRYGB, the multiple models yielded a success threshold range of 13.7 to 15.2 kg/m2 .Conclusions: This study established a preliminary efficacy success threshold for rDBS to be cost-effective for severe obesity, and results from randomized controlled trials are needed. This analysis allows for interpretation of the economic impact of advancing rDBS for obesity in light of ongoing trial results and suggests an attainable threshold is needed for cost-effectiveness. [ABSTRACT FROM AUTHOR]

Introduction: Extracorporeal shock wave lithotripsy (ESWL) is an effective treatment for urolithiasis. Tamsulosin is capable of causing dilation and facilitating the migration of stones. The aim of this study is to evaluate the efficacy of adjuvant treatment with tamsulosin for improving the stone-free rate after a single session of ESWL in the treatment of kidney stones.Methods: This is a randomized, nonplacebo-controlled study with a sample of 60 adults with a single radiopaque kidney stone of 5-20 mm in diameter. After the ESWL session, the patients were divided into two groups. The control group received standard treatment for analgesia consisting of oral diclofenac (75 mg/12 h) as needed. The tamsulosin group received standard treatment for analgesia plus oral tamsulosin (0.4 mg/day) for eight weeks. In both groups, stone-free status was determined using a CT scan eight weeks after ESWL. The protocol of this study was registered with ClinicalTrials.gov, identifier: NCT04819828.Results: Only 57 patients completed the study (28 tamsulosin and 29 control). Overall, the average stone diameter was 11.42 ± 4.52 mm. The stone-free rate was 50.88% (29 of 57) overall, 53.57% (15 of 28) for the tamsulosin group, and 48.27% (14 of 29) for the control group (p = 0.680). The estimated relative risk in favor of the tamsulosin group to achieve a stone-free status was 1.11 (95% CI 0.67-1.9). The estimated number needed to treat to achieve a single patient with renal stone-free status after eight weeks of ESWL adjuvant treatment with tamsulosin was 19.Conclusion: Our findings suggest that tamsulosin as adjuvant treatment after a single ESWL session is well tolerated and safe, but it does not increase the stone-free rate in patients with a single radiopaque renal stone of 5-20 mm in diameter. Our results may support the use of tamsulosin with ESWL in the case of patients with a single radiopaque renal stone of 11-20 mm in diameter based on an apparent higher stone-free rate and a low rate of complications. [ABSTRACT FROM AUTHOR]

Rationale: The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute-walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. Objectives: This post hoc analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Methods: Patients enrolled in INCREASE were analyzed for disease progression events, defined as at least 15% decline in 6-minute-walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, at least 10% decline in forced vital capacity, or death during the duration of the 16-week study. Measurements and Main Results: In total, 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared with 215 events (109/163 patients, 67%) in the placebo group (P = 0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute-walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), FVC decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events), and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared with those receiving the placebo (35 vs. 58, 22% vs. 36%; P = 0.005). Conclusions: Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared with patients receiving placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Tibial plateau fracture is a common fracture encountered in the clinic.Objective: This study determined the optimal timing and surgical approach for patients with tibial plateau fracture.Methods: Fifty-two patients with complex tibial plateau fractures were treated in our hospital (the People's Hospital of Zhongjiang County) between 2013 and 2015. These patients were recruited as participants in this study; all patients were randomly allocated into two groups of 26 patients each. Patients in Group 1 underwent single-incision, single-plate knee surgeries via an antero-lateral approach, and patients in Group 2 underwent anterior median incisions of the knee for double-plate surgeries. The effects of the approaches were compared and analyzed.Results: The best time to perform surgery was 6-8 days post-injury. The anterior median incision, double-plate method approach was better than the antero-lateral, single-incision, single-plate method. For the former method, the healing among middle-aged and young patients was better than that of elderly patients, and that healing of men was slightly better than that of female patients. However, the degree of healing among patients was > 80% at 5 months postoperatively. The purpose of surgical management has been fully achieved.Conclusion: The optimal timing of surgery for patients with complex tibial plateau fractures is 6-8 days post-injury. The surgical approach needs to be determined based on the actual condition of the patient. However, the treatment effect of an anterior median incision, double-plate method is better, and the recovery rate may approach 80% at 5 months postoperatively. [ABSTRACT FROM AUTHOR]

With the availability of limited resources, innovation for improved statistical method for the design and analysis of randomized controlled trials (RCTs) is of paramount importance for newer and better treatment discovery for any therapeutic area. Although clinical efficacy is almost always the primary evaluating criteria to measure any beneficial effect of a treatment, there are several important other factors (e.g., side effects, cost burden, less debilitating, less intensive, etc.), which can permit some less efficacious treatment options favorable to a subgroup of patients. This leads to non-inferiority (NI) testing. The objective of NI trial is to show that an experimental treatment is not worse than an active reference treatment by more than a pre-specified margin. Traditional NI trials do not include a placebo arm for ethical reason; however, this necessitates stringent and often unverifiable assumptions. On the other hand, three-arm NI trials consisting of placebo, reference, and experimental treatment, can simultaneously test the superiority of the reference over placebo and NI of experimental treatment over the reference. In this article, we proposed both novel Frequentist and Bayesian procedures for testing NI in the three-arm trial with Poisson distributed count outcome. RCTs with count data as the primary outcome are quite common in various disease areas such as lesion count in cancer trials, relapses in multiple sclerosis, dermatology, neurology, cardiovascular research, adverse event count, etc. We first propose an improved Frequentist approach, which is then followed by it's Bayesian version. Bayesian methods have natural advantage in any active-control trials, including NI trial when substantial historical information is available for placebo and established reference treatment. In addition, we discuss sample size calculation and draw an interesting connection between the two paradigms. [ABSTRACT FROM AUTHOR]

Background: Rectal gonorrhoea is a common sexually transmitted infection with increasing antimicrobial resistance requiring optimization of available treatments.Objectives: This systematic review aimed to assess the efficacy of current treatments, previously trialled treatments and new emerging treatments for rectal Neisseria gonorrhoeae (NG).Methods: Online bibliographic databases were search from 1 January 1946 to 14 August 2020. All randomized controlled trials (RCTs) with rectal NG data among participants aged 15 years or above and published in English were included. Random effects meta-analyses were used to estimate overall treatment efficacy, defined as microbiological cure. Sub-group analyses included stratifying by diagnostic assay, by dual versus monotherapy, and by currently recommended treatments (e.g. ceftriaxone ± azithromycin) versus previously trialled but not recommended treatments (e.g. amoxicillin) versus emerging treatments (e.g. zoliflodacin). The study protocol was registered on PROSPERO (CRD42020202998).Results: 54 studies including 1813 participants and 44 treatment regimens were identified. The overall summary treatment efficacy for rectal NG was 100.0% (95% CI: 99.9%-100.0%; I2 = 0.0%; P = 0.86). Efficacy estimates for monotherapies (100.0%; 95% CI: 99.88%-100.0%; I2 = 0.00%; P = 0.97) and dual therapies (100.0%; 95% CI: 97.65%-100.0%; I2 = 56.24%; P = 0.03) were similar. Efficacy was highest for current treatments (100.00%; 95% CI: 99.96%-100.00%; I2 = 0.00%; P = 0.98) versus emerging treatments (97.16%; 95% CI: 86.79%-100.00%; I2 = 0.00%; P = 0.84). There were no trials exclusively investigating rectal NG and small sample size was a limitation in most trials.Conclusions: Currently recommended treatments containing ceftriaxone, as mono or dual therapy, are effective. Emerging drugs such as zoliflodacin may be potentially useful for rectal NG but further data are needed. [ABSTRACT FROM AUTHOR]

Background: Modified sutureless and glue-free method is an effective and novel surgical approach for pterygium. We aim to evaluate optical quality in pterygium treated with the new method and investigate the clinical application of the Optical Quality Analysis System (OQAS) and Anterior segment optical coherence tomography (AS-OCT) to evaluate the pterygium surgery.Methods: A total of 52 eyes of 52 patients with pterygium were randomly divided into 2 groups. After surgical excision, the bare sclera was placed with a tight fit limbal conjunctival autograft fixed via the modified sutureless and glue-free method in group 1 (26 eyes) and conventional sutures in group 2 (26 eyes). Objective scattering index (OSI), modulation transfer function (MTF) and Strehl ratio (SR) were measured using OQAS in both groups during the perioperative period. Pterygium diameter was measured on AS-OCT. Ocular surface disease index (OSDI) questionnaire also was used.Results: The group 1 had significantly lower mean OSI, higher mean MTF, and higher mean SR at 1 month and 3 months after surgery (p < 0.05). The group 1 had significantly lower mean OSDI at 1 month (p < 0.05), while was similar to group 2 at 3 months (p > 0.05). Pterygium diameter positively correlated with OSI (r = 0.528, p < 0.001), while it negatively correlated with MTF (r = - 0.501, p < 0.001) and SR (r = - 0.174, p = 0.217) before operation.Conclusions: The modified sutureless and glue-free method might be more advantageous in improving the optical quality during early postoperative recovery times and pterygium diameter affected optical quality. OQAS can be reliably used to evaluate postoperative outcomes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether 1% aqueous chlorhexidine gluconate (CHG) when compared with 2% aqueous chlorhexidine gluconate is non-inferior for neonatal skin antisepsis.Design: Parallel, blinded, non-inferiority randomised trial.Setting: Level III, academic, neonatal intensive care unit.Patients: Infants born at 260/7 to 426/7 weeks of gestation from June 2019 to December 2019.Interventions: Participants were randomised to skin antisepsis by either 1% aqueous CHG or 2% aqueous CHG.Main Outcome Measures: The primary outcome was the proportion of negative skin swab cultures after skin antisepsis. Secondary outcomes were local skin reactions at 0, 6, 12 and 24 hours and plasma chlorhexidine levels in a subset of the study population.Results: A total of 308 neonates with a median gestation age of 34 (31-37) weeks and mean birth weight of 2029 g were randomised on 685 occasions (1% CHG: n=341; 2% CHG: n=344). 93.0% of the post-antisepsis skin swabs were sterile in 1% CHG group compared with 95.6% of the swabs in the 2% CHG group (risk difference -2.7%, 95% CI -6.2% to +0.8%). The lower bound of 95% CI crossed the pre-specified absolute non-inferiority limit of 5%. Neonates developed mild dermatitis on 16 (2.3%) occasions. There was no significant difference in median plasma CHG levels in the two groups, 19.6 (12.5-36.4) and 12.6 (8.7-26.6) ng/mL, respectively.Conclusions: Application of 1% aqueous CHG was not shown to be non-inferior to 2% chlorhexidine aqueous for skin antisepsis in neonates. There were no severe skin-related adverse events in either of the two groups.Trial Registration Number: CTRI/2019/06/019822; (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=33453&EncHid=&userName=CTRI/2019/06/019822). [ABSTRACT FROM AUTHOR]

Background: Current pharmacological and behavioral treatment options for mild cognitive impairment (MCI) are limited, motivating a search for alternative therapies that might slow the progression of cognitive decline.Objective: We investigated the effectiveness of a cognition-focused mindfulness-based intervention.Methods: An open-label, three arm randomized controlled trial was conducted at a public tertiary medical center. Older persons (ages 45-75; N = 76) diagnosed with MCI were recruited and randomized into either mindfulness-based training (MBT), cognitive rehabilitation therapy (CRT), or treatment as usual (TAU). Participants in the intervention arms received 8 weekly 2-h sessions delivered in a group setting and engaged in home practice. Primary outcomes measures included changes in index scores for attention, immediate memory, and delayed memory as measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Depression was a secondary outcome.Results: Using intent-to-treat analysis, we found that participants receiving MBT showed significant improvements in global cognition (d = 0.26; [95%CI 0.03-0.56]) and delayed memory (d = 0.36; [95%CI 0.17-0.57]), with significantly greater improvements in delayed memory than CRT (ηp2 = 0.10). However, there was no benefit of MBT over TAU. No change in depression was observed in the MBT group. Reductions in depression were associated with improvements in cognitive functioning in the MBT group only.Conclusion: Our results suggest that a cognition-focused MBT did not improve cognitive functioning in MCI patients substantially more than spontaneous reversion rates, possibly as mood symptoms were not significantly alleviated in this group. [ABSTRACT FROM AUTHOR]

The primary analysis of randomized screening trials for cancer typically adheres to the intention-to-screen principle, measuring cancer-specific mortality reductions between screening and control arms. These mortality reductions result from a combination of the screening regimen, screening technology and the effect of the early, screening-induced, treatment. This motivates addressing these different aspects separately. Here we are interested in the causal effect of early versus delayed treatments on cancer mortality among the screening-detectable subgroup, which under certain assumptions is estimable from conventional randomized screening trial using instrumental variable type methods. To define the causal effect of interest, we formulate a simplified structural multi-state model for screening trials, based on a hypothetical intervention trial where screening detected individuals would be randomized into early versus delayed treatments. The cancer-specific mortality reductions after screening detection are quantified by a cause-specific hazard ratio. For this, we propose two estimators, based on an estimating equation and a likelihood expression. The methods extend existing instrumental variable methods for time-to-event and competing risks outcomes to time-dependent intermediate variables. Using the multi-state model as the basis of a data generating mechanism, we investigate the performance of the new estimators through simulation studies. In addition, we illustrate the proposed method in the context of CT screening for lung cancer using the US National Lung Screening Trial data. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) preventive therapy (TPT) is an essential component of care for people living with HIV (PLHIV). We compared efficacy, safety, completion, and drug-resistant TB risk for currently recommended TPT regimens through a systematic review and network meta-analysis (NMA) of randomized trials.Methods and Findings: We searched MEDLINE, Embase, and the Cochrane Library from inception through June 9, 2020 for randomized controlled trials (RCTs) comparing 2 or more TPT regimens (or placebo/no treatment) in PLHIV. Two independent reviewers evaluated eligibility, extracted data, and assessed the risk of bias. We grouped TPT strategies as follows: placebo/no treatment, 6 to 12 months of isoniazid, 24 to 72 months of isoniazid, and rifamycin-containing regimens. A frequentist NMA (using graph theory) was carried out for the outcomes of development of TB disease, all-cause mortality, and grade 3 or worse hepatotoxicity. For other outcomes, graphical descriptions or traditional pairwise meta-analyses were carried out as appropriate. The potential role of confounding variables for TB disease and all-cause mortality was assessed through stratified analyses. A total of 6,466 unique studies were screened, and 157 full texts were assessed for eligibility. Of these, 20 studies (reporting 16 randomized trials) were included. The median sample size was 616 (interquartile range [IQR], 317 to 1,892). Eight were conducted in Africa, 3 in Europe, 3 in the Americas, and 2 included sites in multiple continents. According to the NMA, 6 to 12 months of isoniazid were no more efficacious in preventing microbiologically confirmed TB than rifamycin-containing regimens (incidence rate ratio [IRR] 1.0, 95% CI 0.8 to 1.4, p = 0.8); however, 6 to 12 months of isoniazid were associated with a higher incidence of all-cause mortality (IRR 1.6, 95% CI 1.2 to 2.0, p = 0.02) and a higher risk of grade 3 or higher hepatotoxicity (risk difference [RD] 8.9, 95% CI 2.8 to 14.9, p = 0.004). Finally, shorter regimens were associated with higher completion rates relative to longer regimens, and we did not find statistically significant differences in the risk of drug-resistant TB between regimens. Study limitations include potential confounding due to differences in posttreatment follow-up time and TB incidence in the study setting on the estimates of incidence of TB or all-cause mortality, as well as an underrepresentation of pregnant women and children.Conclusions: Rifamycin-containing regimens appear safer and at least as effective as isoniazid regimens in preventing TB and death and should be considered part of routine care in PLHIV. Knowledge gaps remain as to which specific rifamycin-containing regimen provides the optimal balance of efficacy, completion, and safety. [ABSTRACT FROM AUTHOR]

Objectives: Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA).Methods: In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26.Results: Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)).Conclusions: In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA.Trial Registration Number: NCT03058900. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the prevalence of stunting differed between an intervention group and a control group and to identify factors associated with the children's linear growth.Design: This was a follow-up study of mother-child pairs who participated in a 2012-2015 cluster randomised controlled trial. Linear mixed effects models were performed to model the children's linear growth and identify the determinants of child linear growth.Setting: The study was conducted in two slums in Nairobi. The intervention group received monthly nutrition education and counselling (NEC) during pregnancy and infancy period.Participants: A birth cohort of 1004 was followed up every 3 months after delivery to the 13th month. However, as a result of dropouts, a total of 438 mother-child pairs participated during the 55-month follow-up. The loss to follow-up baseline characteristics did not differ from those included for analysis.Results: Length-for-age z-scores decreased from birth to the 13th month, mean -1·42 (sd 2·04), with the control group (33·5 %) reporting a significantly higher prevalence of stunting than the intervention group (28·6 %). Conversely, the scores increased in the 55th month, mean -0·89 (sd 1·04), with significantly more males (16·5 %) stunted in the control group than in the intervention group (8·3 %). Being in the control group, being a male child, often vomiting/regurgitating food, mother's stature of <154 cm and early weaning were negatively associated with children's linear growth.Conclusions: Home-based maternal NEC reduced stunting among under five years; however, the long-term benefits of this intervention on children's health need to be elucidated. [ABSTRACT FROM AUTHOR]

Background: During the period of hospitalization, patients can develop functional decline. The main aim of our study was to assess the natural trajectory of each activity of daily living (ADL) and to assess how in-hospital exercise could influence short-term trajectory of ADLs.Method: Acutely hospitalized patients (n = 297, 56.5% women) were randomly assigned to the intervention or control (usual care) group within the first 48 hours of admission. An exercise training program was prescribed in 2 daily sessions (morning and evening) of 20 minutes duration during 5-7 consecutive days for the intervention group. The primary endpoint was the change in every ADL (assessed with the Barthel Index) from 2 weeks before admission to hospital discharge.Results: Acute hospitalization per se led to significant in-patient's functional ability impairment in ADLs during hospitalization, whereas the exercise intervention reversed this trend (3.7 points; 95% CI: 0.5-6.8 points). After analyzing the trajectory of each one of the ADLs, patients in the control group significantly worsened all activities, but with a different degree of loss. For the between-group analysis, significant differences were obtained in many ADLs including bathing, dressing, grooming, bladder control, toilet use, transfers, mobility, and climbing stairs (p < .05). The control group had the greatest impairment in all domains analyzed (ie, feeding, bathing, dressing, grooming, bowel control, bladder control, toilet use, transfers, mobility, and climbing stairs; p < .05).Conclusions: An individualized multicomponent exercise training program in older adults is effective to reverse the loss of specific ADLs that frequently occurs during hospitalization. Each patient profile should receive an individualized prescription of exercise during hospitalizations.Clinical Trials Registration Number: NCT02300896. [ABSTRACT FROM AUTHOR]

Background: The purpose of this follow up study was to determine if a xenogeneic collagen matrix (CMX) is as effective as free gingival graft (FGG) in preventing further recession 6+ years following vestibuloplasty.Methods: This study was a single-blind (examiner), randomized, controlled, split-mouth study of 30 subjects with insufficient zones of KT (< 2 mm), associated with at least two, paired teeth. The study utilized a within subject treatment comparison to examine non-inferiority according to primary and secondary endpoints 6+ years after therapy. The original study primary efficacy endpoint was keratinized tissue width (KTw); however, in this report, prevention of recession (Rec) was also examined, along with traditional, secondary clinical measures, histopathology of mucosal biopsies and exploratory, patient reported outcomes (PROs) for pain and satisfaction.Results: A total of 23 of the 30 original, study patients were available for 6 to 8-year postoperative assessment, and these patients were representative of the original patient population. For preventing further Rec, CMX was not inferior to FGG (ΔRec = -0.07 ± 1.26 mm for CMX and -0.17 ± 0.78 mm for FGG, P = 0.710). There were no adverse results observed, and histological assessment indicated normal, keratinized gingiva for both therapies. Tissue texture and color match to surrounding, native tissues were significantly better for CMX, and patients preferred CMX over FGG therapy.Conclusions: CMX appears to be a suitable substitute for FGG 6+ years after therapy. [ABSTRACT FROM AUTHOR]

Psychological distress is common in persons with traumatic brain injury (TBI) but treatments remain underdeveloped. This randomized controlled trial of Acceptance and Commitment Therapy (ACT) was designed to address this gap. Ninety-three persons with medically-documented complicated mild to severe TBI, normal-to-mildly impaired memory, and clinically significant psychological distress in the chronic phase of recovery were randomized to receive eight weeks of ACT (manualized with adaptations to address TBI-related cognitive impairments) or a single session of needs assessment, brief counseling/education, and referral. The ACT group showed significantly greater reduction of psychological distress (Brief Symptom Inventory 18) and demonstrated improvements in psychological flexibility and commitment to action (Acceptance and Action Questionnaire-II (AAQ-II) scores). The number of treatment responders (post-treatment BSI 18 GSI T scores <63) was larger in the ACT group than in the control group. Entry of AAQ-II scores into the model of between-group differences in BSI 18 GSI T scores indicated that core ACT processes explained the variance in treatment group outcomes. Provision of ACT reduces psychological distress in persons with TBI in the chronic phase of recovery when adaptations are made to accommodate TBI-related cognitive impairments. Additional clinical trials with a structurally equivalent control group are needed. [ABSTRACT FROM AUTHOR]

Background: Irreversible electroporation (IRE) is a local ablation technique utilizing high voltage, low energy direct current to create nanopores in cell membrane which disrupt homeostasis and leads to cell death. Previous reports have suggested IRE may have a role in treating borderline resectable and unresectable Stage 3 pancreatic tumors.Methods: Patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) will be enrolled in either a randomized, controlled, multicenter trial (RCT) or a multicenter registry study. Subjects enrolled in the RCT must have no evidence of disease progression after 3 months of modified FOLFIRINOX (mFOLFIRINOX) treatment prior to being randomization to either a control or IRE arm. Post-induction and post-IRE treatment for the control and IRE arms, respectively, will be left to the discretion of the treating physician. The RCT will enroll 528 subjects with 264 per arm and include up to 15 sites. All subjects will be followed for at least 24 months or until death. The registry study will include two cohorts of patients with Stage 3 PDAC, patients who received institutional standard of care (SOC) alone and those treated with IRE in addition to SOC. Both cohorts will be required to have undergone at least 3 months of SOC without progression prior to enrollment. The registry study will enroll 532 patients with 266 patients in each arm. All patients will be followed for at least 24 months or until death. The primary efficacy endpoint for both studies will be overall survival (OS). Co-primary safety endpoints will be 1) time from randomization or enrollment in the registry to death or new onset of Grade 4 adverse event (AE), and (2 high-grade complications defined as any AE or serious AE (SAE) with a CTCAE v5.0 grade of 3 or higher. Secondary endpoints will include progression-free survival, cancer-related pain, quality of life, and procedure-related pain for the IRE arm only.Discussion: These studies are intended to provide Level 1 clinical evidence and real-world data demonstrating the clinical utility and safety of the use of IRE in combination with chemotherapy in patients with Stage 3 PDAC.Trial Registration: Clinicaltrials.gov NCT03899636 and NCT03899649. Registered April 2, 2019. Food and Drug Administration (FDA) Investigational Device Exemption (IDE) trial G180278 approved on May 3, 2019. [ABSTRACT FROM AUTHOR]